INTRODUCTION: Management of multiple sclerosis (MS) revolves around timely initiation of effective disease-modifying therapy. Here we investigate the additive predictive value of age-adjusted normalised neurofilament light chain (NfL) concentrations when combined with a clinicodemographic model of treatment response. METHODS: Data were obtained from three sources: the University Hospital Basel, the SET cohort in Prague, and EIMS and IMSE cohorts from Sweden. NfL samples were collected within 90 days of baseline, age-adjusted and normalised using a reference population. Principal component analysis reduced the dimensionality of clinicodemographic predictors. Cox proportional hazards models estimated cumulative hazards of relapse, 6-month confirmed disability worsening and 9-month confirmed disability improvement, with and without NfL. Uno's concordance index compared prediction accuracy across pooled and treatment-specific models. RESULTS: The study included 1716 individuals across three therapies: interferon β (n = 554), fingolimod (n = 307) and natalizumab (n = 369). Clinicodemographic characteristics were associated with relapse and disability outcomes. While NfL showed no association in the pooled cohort, in the natalizumab group, higher NfL predicted lower probability of disability improvement (HR = 0.819, 95% CI: 0.814-0.823). Pooled models predicted outcomes with moderate accuracy (relapse: 63.4%, disability worsening: 56.4%, improvement: 67.7%), with minimal contribution from NfL. In treatment-specific models, NfL-inclusive accuracy ranged from 51.3%-62.2% (relapse), 54.3%-60.3% (worsening) and 65%-67.9% (improvement), closely matching models without NfL. CONCLUSION: In well-characterised MS patients treated with interferon β, fingolimod or natalizumab, clinicodemographic information provides modest prognostic value; however, NfL adds minimal incremental utility.

Brain and Mind Centre the University of Sydney Sydney New South Wales Australia

Centre for Molecular Medicine Karolinska University Hospital Stockholm Sweden

Clinical Trial Unit Department of Clinical Research University Hospital Basel University of Basel Basel Switzerland

Core Department of Medicine The University of Melbourne Melbourne Victoria Australia

Department of Clinical Neuroscience Karolinska Institutet Stockholm Sweden

Department of Neurology and Center of Clinical Neuroscience 1st Faculty of Medicine Charles University and General University Hospital Prague Czech Republic

Department of Neurology Box Hill Hospital Melbourne Australia

Melbourne School of Psychological Sciences the University of Melbourne Australia

Menzies Institute for Medical Research University of Tasmania Hobart Tasmania Australia

Neuroimmunology Centre Department of Neurology The Royal Melbourne Hospital Melbourne Victoria Australia

Neurologic Clinic and Policlinic MS Centre and Research Centre for Clinical Neuroimmunology and Neuroscience Basel University of Basel Basel Switzerland

Sydney Neuroimaging Analysis Centre Camperdown New South Wales Australia

The Florey Institute of Neuroscience and Mental Health University of Melbourne Parkville Victoria Australia

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